What are the 3 main jobs of the innate immune system?
3 main jobs of the innate immune system:
- Recognition
- Amplification
- Response
What does “recognition” involve within the innate immune system?
Recognition – distinguishing good from bad
- Pattern recognition
- Foreign / alarm (cancer) / damage / innate vs adaptive (both use innate systems) / lectins & collectins (MBL)
- Dedicated Pattern Recognition Receptors (PRRs)
- Amplification
- Intracellular – adaptors, kinases, result in ca+ influx, transcription activation
- Extracellular – chemokines, complement
- Response
- Inflammation – vascular permeability, increased blood flow, endothelial activation
- Innate effector – soluble proteins (complement, antimicrobials, apoptosis) / phagocytosis
- Initiation of adaptive immunity – cytokines (polarize t-cells & increase adhesion)
- Chemokines – recruit adaptive cells
- Co-stimulation to adaptive immune cells
- Ag processing
What are pattern recognition receptors?
- In order to detect pathogens such as bacteria and viruses the immune system is equipped with receptors called pattern recognition receptors (PRRs)
- The PRRs are a key element of the innate immune system.
- They are proteins expressed, mainly, by cells of the innate immune system, such as:
- dendritic cells
- macrophages
- monocytes
- neutrophils
- epithelial cells
The PRRs are divided into four families:
- Toll-like receptors (TLR)
- Nucleotide-binding oligomerization domain-like receptors (NLR)
- C-type lectin receptors (CLR)
- RIG-1 like receptors (RLR)
- These receptors are strategically localized in the cell. There are present at the cell surface to recognize extracellular pathogens such as bacteria or fungi, in the endosomes where they sense intracellular invaders such as viruses and finally in the cytoplasm.
Name the 5 main families of pattern recognition receptors (PRRs)
The 5 families of pattern recognition receptors
1) Those that contain Leucine rich repeat (LRR) segments
- Toll-like receptors (TLRs)
- Nod-like receptors (NLRs)
2) RNA-sensing RIG-I-like receptors (RLRs)
* Retinoic acid inducible genes I (RIG-I)
3) DExD/Hbox Helicases (DDX)
4) Pyrin and HIN domain-containing (PYHIN)
5) C-type lectin receptors (CLRs)
* Dectin-1
Where can these pattern recognition receptors (PRRs) be found?
They are proteins expressed, mainly, by cells of the innate immune system, such as dendritic cells, macrophages, monocytes, neutrophils and epithelial cells
Pattern recognition receptors are found on:
Cell surfaces = TLRs, CLRs
Endosomal = TLRs
Cytoplasmic = RLRs, NLRs
What activates pattern recognition receptors (PRRs) – what are they looking for?
The immune system is more concerned with ‘danger’ or ‘damage’ than with the distinction between self and non‐sel
It defines danger as anything that causes tissue stress or destruction
- Pathogen‐associated molecular pattern molecules (PAMPs) are derived from microorganisms and recognized by pattern recognition receptor (PRR)‐bearing cells of the innate immune system as well as many epithelial cells
- In contrast, damage‐associated molecular pattern molecules (DAMPs) are cell‐derived, and initiate and perpetuate immunity in response to trauma, ischemia, and tissue damage, either in the absence or presence of pathogenic infection
- Most PAMPs and DAMPs serve as so‐called ‘Signal 0s’ that bind specific receptors [Toll‐like receptors, NOD‐like receptors, RIG‐I‐like receptors, AIM2‐like receptors, and the receptor for advanced glycation end products (RAGE)] to promote cell survival or destruction
What are PAMPs?
Pathogen‐associated molecular pattern molecules (PAMPs) are derived from microorganisms and recognized by pattern recognition receptor (PRR)‐bearing cells of the innate immune system as well as many epithelial cells.
(PAMPs) enter the cell via phagocytosis or pores
Major types of PAMPs are:
- Microbial nucleic acids including DNA (e.g. unmethylated CpG motifs)
- Bacterial flagella
- double‐stranded RNA (dsRNA)
- single‐stranded RNA (ssRNA)
- 5′‐triphosphate RNA
- Lipoproteins
- surface glycoproteins
- membrane components [peptidoglycans, lipoteichoic acid, lipopolysaccharide (LPS), and glycosylphosphatidylinositol]
What are DAMPs?
Damage‐associated molecular pattern molecules (DAMPs) are cell‐derived proteins that initiate and perpetuate immunity in response to trauma, ischemia, cancer, and tissue damage, either in the absence or presence of pathogenic infection
(DAMPs) are associated with cell stress
- DAMPs are localized within the:
- nucleus and cytoplasm (HMGB1)
- cytoplasm alone (S100 proteins)
- exosomes [heat shock proteins (HSPs)]
- extracellular matrix (hyaluronic acid)
- and in plasma components such as complement (C3a, C4a, and C5a).
- Examples of non‐protein DAMPs include:
- ATP, uric acid, heparin sulfate, RNA, and DNA.
- DAMPs can also be mimicked by release of intracellular mitochondria, consisting of formyl peptides and mitochondrial DNA (with CpG DNA repeats)
How many TLRs are there?
How many TLRs are there?
11
- though humans only have TLR 1-10
- rodents have TLR 11
What types of ligands to TLRs recognize?
What types of ligands to TLRs recognize?
Both PAMPs and DAMP
- PAMP – pathogen associated molecular pattern
- DAMP – danger associated molecular pattern
**The only DAMP that is recognized by TLRs = HSP70 (by TLR 2 / 6 / 4)
**All other things that are recognized by TLRs = PAMPs
What TLRs are found on the surface?
What TLRs are found on the surface?
- All except TLRs 3 / 7 / 8 / 9 (which are found in the endosomes)
- TLRs 1/2/4/5/6/10
**TLR 37-89 (endosomal)
What is the most important thing that TLRs eventually lead to?
Activation of NF-kB
- TLRs use NF-kB as their big transcription factor
- Think it as a funnel to get to NF-KB
NF-kB is essential for innate & adaptive responses
- Without NF-kB, you dont get fxnl T or B-cells
- If B-cells can’t activate NF-kB, they can’t develop from Pro-B cell to Pre-B cells (agammaglobulinemia)
- NF-κB allows T-cell development, maturation, and proliferation
- When the T-cell receptor is stimulated, Lck leads to ZAP70 recruitment, which stimulates LAT and PLC-γ, which causes activation of PKC. PKC causes a cascade of phosphorylation events, leading to activation of NF-kB
What other transcription factors are activated as the result of TLR stimulation?
Though NF-kB is the most important…
Other gene transcription factors are also activated by TLRs
- AP-1 = leads to proinflammatory cytokines
- IRF5 = leads to proinflammatory cytokines
- IRF-3 = leads to IFN-B, chemokines
- IRF7 = leads to production of IFN-alpha & IFN-B, chemokines
What cytokines does the activation of NF-kB lead to?
NF-kB turns on pro-inflammatory cytokines – know
- TNF
- IL-1
- IL-6
- IL-12
Which TLRs are found together in groups / share receptors?
Which TLRs are found together in groups / share receptors?
TLRs
- (1 / 2 / 6 ) are found in a grouping and signal through a similar protein (TIRAP) to MyD88
- 1 & 2 look for similar ligands, and fxn on similar bacteria
- 2 & 6 look for similar ligands, and fxn on similar bacteria
- (5 and 10 ) were thought to be in a grouping and signal through a similar protein (TIRAP) to MyD88
- new research suggests 10 may be a loner…which would make TLR5 one too
- TLR 11 is only found in rodents
- (7 / 8 / 9) are found in a grouping and signal through a similar protein (TIRAP) to MyD88
- 7 / 8 TLRs look for similar ligands, and fxn on similar viruses or synthetic particles
- TLR 9 looks for different ligands, and fxns on different bacteria and viruses
**TLR 4 = loner (on the cell surface)
**TLR 3 = loner (in the endosome)
Why is TLR 3 special?
Why is TLR 3 special?
- It sits alone inside the cell (within the endosome) – not with the other intracellular / endosomal based TLRs ( 7/8/9)
- Also is the only TLR that doesn’t signal through the MyD88 pathway
- TLR 3 uses the TRIF pathway to activate TRAF6
- All TLRs eventually activate TRAF6, though all the others (except TLR3) use MyD88 to activate IRAK4 (which eventually activates TRAF6)
TLR 1
Where is it found?
What is it’s ligand that it looks for / is activated by?
What does it fight against / what is the source of it’s activating ligand?
TLR 1
Where is it found?
- Cell surface
- Is in a grouping with 1 / 2 / 6
What is it’s ligand that it looks for / is activated by?
- Lipoarabinomannan (Lipo-arabino-mannan)
- Triacyl lipopeptides
What does it fight against / what is the source of it’s activating ligand?
- Mycobacteria
- Bacteria
TLR 2
Where is it found?
What is it’s ligand that it looks for / is activated by?
What does it fight against / what is the source of it’s activating ligand?
TLR 2
Where is it found?
- Cell surface
- Is in a grouping with 1 / 2 / 6
What is it’s ligand that it looks for / is activated by?
- Lipoarabinomannan (Lipo-arabino-mannan)
- Triacyl lipopeptides
- Diacyl lipopeptides (different than TLR1 – but shared with TLR6)
- Zymosan
- Peptidoglycan
- HSP70 (**the only DAMP recognized by TLRs)
What does it fight against / what is the source of it’s activating ligand?
- Mycobacteria
- Mycoplasma (Diacyl lipopeptides)
- Bacteria
- Fungi
- Host
TLR 3
Where is it found?
What is it’s ligand that it looks for / is activated by?
What does it fight against / what is the source of it’s activating ligand?
TLR 3
Where is it found?
- Endosomal
- It’s a loner (not found with the other endosomal TLRs 7 / 8 / 9)
What is it’s ligand that it looks for / is activated by?
- ds RNA
What does it fight against / what is the source of it’s activating ligand?
-Viruses
**TLR 3 is special b/c it uses TRIF (via RIP1) to activate TRAF6 – the only TLR to not use MyD88
TLR 4
Where is it found?
What is it’s ligand that it looks for / is activated by?
What does it fight against / what is the source of it’s activating ligand?
TLR 4
Where is it found?
- Cell surface
- It’s a loner (not in a group 1/2/6 or 5/10/11)
What is it’s ligand that it looks for / is activated by?
- Lipopolysaccharide
- RSV fusion protein
- HSP70 (**the only DAMP recognized by TLRs)
What does it fight against / what is the source of it’s activating ligand?
- Gram negative bacteria
- RSV
- Host
TLR 5
Where is it found?
What is it’s ligand that it looks for / is activated by?
What does it fight against / what is the source of it’s activating ligand?
TLR 5
Where is it found?
- Cell surface
- possibly is in a grouping with 5 / 10 ?? – 10 may be a loner…which would make 5 one as well
What is it’s ligand that it looks for / is activated by?
- Flagellin
What does it fight against / what is the source of it’s activating ligand?
- Flagelated Bacteria
TLR 6
Where is it found?
What is it’s ligand that it looks for / is activated by?
What does it fight against / what is the source of it’s activating ligand?
TLR 6
Where is it found?
- Cell surface
- Is in a grouping with 1 / 2 / 6
What is it’s ligand that it looks for / is activated by?
- Diacyl lipopeptides (different than TLR1 – but shared with TLR2)
- Zymosan
- Peptidoglycan
- HSP70 (**the only DAMP recognized by TLRs)
What does it fight against / what is the source of it’s activating ligand?
- Mycoplasma (Diacyl lipopeptides)
- Bacteria
- Fungi
- Host
TLR 7
Where is it found?
What is it’s ligand that it looks for / is activated by?
What does it fight against / what is the source of it’s activating ligand?
TLR 7
Where is it found?
- Endosome
- Is in a grouping with 7 / 8 / 9
What is it’s ligand that it looks for / is activated by?
- ss GU RNA
- short ds RNA
- Imidazaoquinolones
What does it fight against / what is the source of it’s activating ligand?
- Viruses
- Synthetic particles
TLR 8
Where is it found?
What is it’s ligand that it looks for / is activated by?
What does it fight against / what is the source of it’s activating ligand?
TLR 8
Where is it found?
- Endosome – shares similar ligands and fxns with TLR 7
- Is in a grouping with 7 / 8 / 9
What is it’s ligand that it looks for / is activated by?
- ss GU RNA
- short ds RNA
- Imidazaoquinolones
What does it fight against / what is the source of it’s activating ligand?
- Viruses
- Synthetic particles
